The present invention relates to cyclohexylurea compounds, to processes for the production thereof, to pharmaceutical preparations containing these compounds and to the use of cyclohexylurea compounds for the production of pharmaceutical preparations.
The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (opioid-receptor-like) receptor (Meunier et al., Nature 377, 1995, p. 532-535), which belongs to the family of opioid receptors, may be found in many regions of the brain and spinal cord and exhibits a high affinity for the ORL1 receptor. The ORL1 receptor is homologous to the μ, κ and δ opioid receptors and the amino acid sequence of the nociceptin peptide exhibits a strong similarity to those of known opioid peptides. Nociceptin-induced activation of the receptor gives rise, via coupling with Gi/o proteins, to inhibition of adenylate cyclase (Meunier et al., Nature 377, 1995, p. 532-535).
On intracerebroventricular administration, nociceptin peptide exhibits pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, p. 792-794). These findings may be explained as inhibition of stress-induced analgesia (Mogil et al., Neuroscience 75, 1996, p. 333-337). In this connection, it has also been possible to demonstrate an anxiolytic activity of the nociceptin (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).
On the other hand, it has also been possible to demonstrate an antinociceptive effect of nociceptin in various animal models, in particular on intrathecal administration. Nociceptin has an antinociceptive action in various pain models, for example in the murine tail-flick test (King et al., Neurosci. Lett., 223, 1997, 113-116). It has likewise proved possible to demonstrate an antinociceptive action of nociceptin in models of neuropathic pain, this action being of particular interest in that the activity of nociceptin increases after axotomy of spinal nerves. This is in contrast to classical opioids, whose activity decreases under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, p. 9685-9694).
The ORL1 receptor is also involved in the regulation of further physiological and pathophysiological processes. These include, inter alia, learning and memorisation (Manabe et al., Nature, 394, 1997, p. 577-581), hearing (Nishi et al., EMBO J., 16, 1997, p. 1858-1864) and many other processes. A review article by Calo et al. (Br. J. Pharmacol., 129, 2000, 1261-1283) provides an overview of the indications or biological processes in which the ORL1 receptor plays or could with a high level of probability play a role. The list includes the following: analgesia, stimulation and regulation of food intake, influence on μ agonists such as morphine, treatment of withdrawal symptoms, reduction of the addictive potential of opioids, anxiolysis, modulation of mobility, memory disorders, epilepsy; modulation of neurotransmitter release, in particular of glutamate, serotonin and dopamine, and thus of neurodegenerative diseases; influence on the cardiovascular system, initiation of erection, diuresis, antinatriuresis, electrolyte balance, arterial blood pressure, water retention diseases, intestinal motility (diarrhoea), relaxing effects on the respiratory tract, micturition reflex (urinary incontinence). The use of agonists and antagonists as anorectics, analgesics (also coadministered with opioids) or nootropics is also discussed.
Compounds which bind to the ORL1 receptor and activate or inhibit it have a correspondingly wide range of potential applications. In addition to this receptor, opioid receptors such as the μ receptor and other subtypes also play a major role, especially in pain therapy, but also in others of the stated indications. It is accordingly favourable if the compound also exhibits activity on these opioid receptors.